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Identification and prognostic analysis of the cetuximab resistance-related gene REV1 in RAS wild-type metastatic colorectal cancer.

ABSTRACT: The survival of patients with RAS wild-type metastatic colorectal cancer (mCRC) has improved markedly since the introduction of cetuximab, which is an anti-epidermal growth factor receptor monoclonal antibody. However, not all RAS wild-type patients respond to cetuximab treatment. Although some genetic alterations associated with cetuximab resistance have been identified, they cannot fully explain all cases of cetuximab resistance. Thus, in this research, we aimed to identify new genetic alterations associated with resistance to this treatment. The study retrospectively analyzed 70 patients diagnosed with RAS wild-type mCRC at our hospital between November 2009 and July 2018. First, five progression-free survival (PFS)-longest and 5 PFS-shortest tumor deoxyribonucleic acid were analyzed by whole-exome sequencing (WES) to identify differentially mutated genes. Then, PFS analysis of the 70 patients was used to verify the correlation between the candidate gene and cetuximab sensitivity. Finally, data from public databases were used to further verify the relationship between the mRNA expression level of the candidate gene and cetuximab responsiveness. The WES results indicated REV1: c.2108G > A was a candidate gene mutation related to the effectiveness of cetuximab. Survival analysis suggested REV1: c.2108G > A was associated with rapid disease progression (median PFS time, REV1 mutant vs. REV1 wild-type: 4.4 months vs. 8.7 months, P = 0.034). Data from the Genomics of Drug Sensitivity in Cancer and the Gene Expression Omnibus databases suggested low REV1 mRNA levels might be related to the poor response of CRC cells and reduced cetuximab efficacy among mCRC patients. In conclusion, REV1 expression levels and the REV1: c.2108G > A mutation may be related to cetuximab resistance in RAS wild-type mCRC.

SUBMITTER: Zhu N

PROVIDER: S-EPMC8263679 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThis study sought to explore the biological significance of genetic variation in RAS wild-type metastatic colorectal cancer (mCRC) in the real world, the difference in the efficacy of cetuximab in the treatment of mCRC with different genetic variants and identify clinical features and new predictors of efficacy.MethodsA retrospective analysis of the data of 60 patients with stage IV mCRC who received cetuximab at The First and Second Affiliated Hospital of Soochow University from 2016 to 2020 was conducted. The patients were divided into the following 3 groups according to the genetic test results: (I) group A (the all-RAS wild-type group); (II) group B (the all-RAS wild-type group with the tumor suppressor gene mutation); and (III) group C (the all-RAS wild-type group with the oncogenic driver gene mutation). A subgroup analysis was conducted to examine left CRC and local intervention, and the progression-free survival (PFS) and overall survival (OS) of the patients were observed.ResultsThe all-RAS wild-type mCRC patients were divided into group A (n=10), group B (including the TP53, APC, PTEN, BRCA2, and SMAD4 variants) (n=42), and group C (including the ERBB2, BRAF, PIK3CA, and RET variants) (n=8). The median PFS of groups A, B, and C were 15.0, 12.0, and 3.0 months, respectively (P=0.007). Fitting sex as a stratified variable to the Cox survival analysis model showed that only the PFS of groups B and C differed significantly (P=0.011). In the left-sided mCRC patients, the median PFS of groups A, B, C were 3.0, 13.0, and 3.0 months, respectively (P=0.009). Among the patients in group B, the median PFS of the metastatic local intervention subgroup was 14.0 months, and the non-local intervention subgroup was 12.0 months (P=0.55). Only the type of combined gene mutation was an independent factor affecting PFS.ConclusionsThe PFS and OS of mCRC patients with all-RAS wild-type and no combined mutations treated with cetuximab were not better than those of patients with combined mutations. Compared to mCRC patients with all-RAS wild-type and oncogenic driver gene mutations, cetuximab significantly prolonged the PFS of all-RAS wild-type patients with the tumor suppressor gene mutations.

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Identification and prognostic analysis of the cetuximab resistance-related gene REV1 in RAS wild-type metastatic colorectal cancer.

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